Friday, December 28, 2012

More Misinformation from the British Press - Smith

More Misinformation from the British Press

Yesterday, an article was published on the front page of a national newspaper in the UK, claiming “proof that statins save millions” and “wonder pill halves heart attack deaths”.

The article was published in the Daily Express newspaper on 27 December 2012, written by Giles Sheldrick. I have formally complained to the editor about the gross inaccuracies the article contains.
The article is based on data published in a recent report from the British Heart Foundation (BHF). The title of this report is Coronary Heart Disease Statistics 2012.

The article in the Daily Express claims that the reduction in heart disease deaths / heart attacks is mostly due to cholesterol lowering statins.

The recent BHF publication (available here) does clearly show that deaths from heart disease have continued to fall, however, nowhere in this publication is there any data to support the claim that statins have played a significant part.

The BHF publication references only one study; a 2004 study referenced on pages 14 and 15 of the publication. This referenced study is freely available here:

It is absolutely clear from this study that the vast majority of the reduction in heart disease deaths was from the reduction in the number of people smoking and improvements in emergency treatments. It had very little to do with statin medications. In fact, if you look at Table 1 of this study, we can see that statins, at best, contributed less than one percent to the reduction in deaths.

The first line of the Daily Express article reads “THE use of statins has halved the number of deaths from heart attacks”. There is no data to support this statement anywhere in the BHF publication or the 2004 study referenced by the BHF.

There are a number of additional points to consider.

The graph below is from another publication from the British Heart Foundation (Coronary Heart Disease Statistics 2008, available here) . If we look at figure 1.4 from page 25, we can see that heart disease deaths have been reducing since the 1970s, but there is no significant change in the graph around 1995. This is important because statin medications first started to be widely prescribed in 1995. If statins were having a significant impact, we would of course expect to see a more dramatic reduction around 1995, but we do not. In fact, some age groups have seen a slowing down of the reduction since the widespread introduction of statins in 1995.

It is important to note that even if statins do very slightly reduce the risk of suffering a heart attack (typically less than one percent reduction in risk), at the same time, these medications increase the risk of dying from other serious diseases. This is particularly the case when statins are used for 'prevention'. All of the clinical trials, where statins have been used for 'prevention' have failed to show any increase in life expectancy. The potential very slight reduction in heart attack risk has always been off-set by an increase in deaths from other causes due to the statin.

Not to mention the fact that around 20 percent of people who take statins experience considerable adverse effects, which in many cases have ruined peoples' lives.
Read the complete article here.

Wednesday, December 26, 2012

Track Your Plaque - Davis

Track Your Plaque

In addition to writing, speaking, and practicing preventive cardiology in Milwaukee, Wisconsin, Dr. Davis is the Medical Director and founder of the Track Your Plaque program for heart disease prevention and reversal. This program was described in the book, Track Your Plaque: The only heart disease prevention program that shows how to use the new heart scans to detect, track, and control coronary plaque, as well as the online program. Wheat elimination, along with the nutritional principles articulated in Wheat Belly, serve as the cornerstone of the heart disease prevention efforts used in the Track Your Plaque program, as well.

Friday, December 21, 2012

Real Life vs. Pharma Company Studies - Kendrick

Real Life vs. Pharma Company Studies

December 21, 2012

At what point, exactly, does credibility snap? When does the difference between what we are told, and what we observe, reach such a state of dissonance that it is no longer possible to believe both. Sometimes it seems the answer is ….never.

Here is one example. The clinical trials on statins found that they have virtually no adverse effects. Or, to be a little more accurate, that adverse events were virtually identical to placebo. Here, for example, is part of the press release from the Heart Protection Study (HPS). This was the last major placebo controlled statin study done in people with already diagnosed cardiovascular disease.

As the benefits of statins are now thought so wonderful it would be considered unethical to do a placebo controlled study anymore. You would be withholding statins from people who need them. Which means that you are not going to get any more evidence in this area – ever again. The HPS results were published around ten years ago, and the press release contained the following

‘Although muscle pain was reported by the participants, this happened about as commonly among those allocated the active simvastatin as among those allocated the placebo tablets. Despite 20,536 randomised patients having been followed for an average of five years, blood tests among people reporting muscle symptoms found only 11 simvastatin-allocated patients and 6 placebo-allocated patients with a rise in the muscle enzyme creatine kinase (CK) to more than 10 times the upper limit of normal Of these, 14 met the definition for “myopathy” (i.e. muscle symptoms associated with such CK elevations) of whom 10 were in the simvastatin group and 4 in the placebo group.’


Teasing these figures out a little more it seems that an extra six people taking simvastatin suffered muscle ‘problems’ than those taking the placebo. This is six people, out of more than ten thousand taking simvastatin. This represents in one thousand seven hundred and eight 1/1708 (over five years).
If this were true, then muscle problems should be exceedingly rare. The average GP with about two hundred of their fifteen hundred patients taking a statin should see a patient with muscle pains/problems about once every twenty five years. At this rate, you would not even know you had a problem.

Yet, wrapped around my copy of the BMJ last week was an advert for rosuvastatin [Crestor]. The strap line shouted out ‘Myalgia on his initial statin?’ [Myalgia is the medical word for muscle pain]. The main message the advert was… ‘If your patient was suffering muscle pains on their initial statin, they should switch to Crestor 5mg.’

Their ‘initial statin’ will almost certainly be Simvastatin 40mg. The drug, and the dose, used in the HPS study. The same drug, and the same dose recommended by the National Institute of Clinical Excellence (NICE).

Now, you do not run an expensive advertising campaign without doing a lot of market research first. What the market research must have told AstraZeneca – who make Crestor – is that a lot of people are suffering muscle pains on 40mg simvastatin.

Which means that simvastatin, which caused no discernible increase in muscle pains in the clinical study…… actually creates such a massive burden of muscle problems that a pharmaceutical campaign is running a major advertising campaign highlighting this, exact, adverse event.

What does this tell us, gentle reader? It tells us many things. Some of which would be considerable slanderous if I said them out loud. The most outstanding thing it tells me is that, although we have all been repeatedly informed that statins have no more side-effects than placebo, I now find that AstraZeneca encouraging doctors to switch statins due to the burden of side-effects.

F Scott Fitzgerald opined that …“The test of a first-rate intelligence is the ability to hold two opposed ideas in the mind at the same time, and still retain the ability to function.’

I would suggest that there comes a point where you have to decide between which idea is right, and which is wrong. With regard to statins, I did this many years ago when I recognised that they cause a gigantic burden of adverse effects, with muscle pain the single most outstanding. I knew that the clinical trials had somehow or another managed to bury this fact.

Yet, when I speak to most doctors they continue to tell me that statins have very few side-effects, as do most opinion leaders. This belief, whilst AstraZeneca starts up an advertising campaign based on side-effects reported by doctors. F Scott Fitzgerland would be impressed by all these first class intellects. I just despair of them.
Read the complete article here.

Thursday, December 20, 2012

Current State of Niacin in Cardiovascular Disease Prevention - JACC

The Current State of Niacin in Cardiovascular Disease Prevention: Title and subTitle BreakA Systematic Review and Meta-Regression

Paul M. Lavigne, MD; Richard H. Karas, MD, PhD


Objectives This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
Conclusions The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.


Although potentially indicative of limited efficacy in select patients, the recently published findings of AIM-HIGH are insufficient to alter the aggregate available data supporting the clinical efficacy of niacin therapy as a means to reduce CVD risk. The present analysis demonstrates the summary effect of niacin across a broad clinical population to confer atheroprotection and cautions against the extension of recent isolated findings to substantially alter overall clinical practice. These results thus underscore the need for further analysis, including that offered by the ongoing HPS2-THRIVE (Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events) trial, to more clearly define the role of niacin in current practice.


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Reas the complete article here.

Wednesday, December 19, 2012

Friday, December 14, 2012

Drug company kills off another cholesterol-modifying drug - Briffa

Drug company kills of another cholesterol-modifying drug
I rarely meet someone who has not heard of cholesterol and does not believe it to be a largely dangerous substance. And increasing number of people seem to be aware of the conventional wisdom regarding the different forms of cholesterol, specifically low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Actually, these names are a bit misleading, as these particles are not cholesterol (though they do contain cholesterol). But, anyway, the conventional wisdom is that LDL-C dumps cholesterol on the inside of our arteries while HDL-C clears cholesterol. As a result, LDL-C and HDL-C are often dubbed ‘bad-’ and ‘good-’ cholesterol.

The most commonly prescribed cholesterol drugs are known as statins, and their main mechanism of action is to lower LDL-C levels. However, other types of cholesterol-modifying drugs exist, including a relatively new class known as cholesterylester transfer protein inhibitors (CEPT inhibitors), which the conversion of supposedly healthy HDL-C into supposedly unhealthy LDL-C. If you believe the conventional wisdom on cholesterol (I don’t), then this should translate into benefits for health with regard cardiovascular disease (e.g. heart disease and stroke).

All this theory is meaningless, however. The only important thing is not the effect drugs (or anything else) have on cholesterol levels, it’s the impact they have on health. Some years back the drug company Pfizer spent in the region of $800 million developing a CEPT inhibitor by the name of torcetrapib. It had ‘positive’ effects on LDL-C and HDL-C levels, but also turned out to kill people. Pfizer promptly and quite rightly ceased development of the drug.

The crashing failure of torcetrapib has not stopped other drug companies seeking to find a commercially viable CEPT inhibitor of their own. More recently, drug company Roche invested in the development of a drug known as dalcetrapib. However, in the middle of this year Roche abandoned plans for further development, and a recently-published study shows us why [1].

In this study, published in the New England Journal of Medicine, almost 16,000 patients who had suffered from ‘acute coronary syndrome’ (e.g. angina or heart attack) were treated with dalcetrapib or placebo for an average of about two and a half years.

These are just the sort of patients one would expect to benefit most from an intervention because, as a group, they would generally be at high risk of future problems. Also, the number of subjects here is huge, and therefore more than big enough to detect any real benefit the drug may have.

The researchers assessed the effects of dalcetrapib using a ‘composite endpoint’ – which essentially means lumping several outcomes together. The composite outcome included death from heart disease, non-fatal heart attack, ischemic stroke (strokes due to blockage of blood vessels rather than bleeding), unstable angina (angina that can come on at rest), and cardiac arrest with resuscitation. The use of composite endpoints ups the odds that a ‘statistically significant’ benefit for a drug will be found (compared to when only one single outcome is chosen).

Biochemical analysis revealed that dalcetrapib did, as expected, have considerable HDL-boosting effect. But the study showed that this drug had no benefits for health at all.

Another interesting thing about the study was that dalcetrapib was found to increase markers of inflammation – a process which is believed to play a key part on the development of heart disease and stroke.

This study was originally designed to run for longer but was terminated early once these results were in. Early termination of studies is known to generally inflate the benefits of drugs and downplay their risks. Who knows what may have happened if they’d continued.

Of course you’re unlikely to hear about the dalcetrapib study because it wasn’t announced with the blaze of publicity usually afforded to more ‘positive’ studies about cholesterol-reducing drugs. But this is often the way with cholesterol-related research in particular: positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.

1. Schwartz GG, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 29 November 2012 (epub)
Read the complete article here.

Monday, December 10, 2012

Scant Evidence That Salt Raises BP - Kaiser

Scant Evidence That Salt Raises BP, Review Finds

The evidence for health benefits associated with salt reduction is controversial and the "concealment of scientific uncertainty" is a mistake, researchers suggested.

Controversy about what effect too much sodium intake has on the body goes back to the early part of the 20th century, according to Ronald Bayer, PhD, and colleagues from Columbia University Mailman School of Public Health in New York City.

But in the last few years, the discourse has reached a fever pitch, they wrote online in Health Affairs.

In 2011, for example, the Journal of the American Medical Association published a study by Stolarz-Skrzypek et al. that found only a weak correlation between salt and blood pressure. An editorial in the Lancet lambasted the JAMA study as "disappointingly weak" and "likely to confuse public perceptions of the importance of salt as a risk factor for high blood pressure, heart disease, and stroke."

Also in 2011, the Cochrane Review published two studies finding little or no relationship with all-cause mortality and salt reduction. The Lancet criticized both the Cochrane Library and the authors, saying, "They have seriously misled the press and thereby the public."

One of those reviews had concluded that "after more than 150 randomized controlled trials and 13 population studies without an obvious signal in favor of sodium reduction, another position could be to accept that such a signal may not exist."

Bayer and colleagues cited several studies that could not find a link between salt intake and elevated blood pressure, including a 1967 study of the Framingham cohort, and Japanese and Scottish reports in the 1980s totalling 15,000 people that concluded the association between sodium and blood pressure is "extremely weak."

The researchers noted that most of the evidence pointed to the weakest of correlations between salt and blood pressure. Yet, the cause to reduce salt was taken up by government agencies with special speed.

They cited a 2010 Institute of Medicine report called "Strategies to Reduce Sodium Intake in the United States." In the report, the IOM claimed that the "harmful relationship of salt with hypertension has been known for 40 years," which Bayer and colleagues argue is debatable -- based on the evidence.

"The [IOM] report was welcomed by the incoming president of the the American Society of Hypertension," the investigators wrote, "who warned that the 'outcomes mafia' might challenge the justification for a regulatory approach."

In 2011, the FDA also called for data and recommendations "that would help it shape regulatory policy on salt in food."

"All the while, skeptics still were asking for the evidence," Bayer and colleagues wrote.
More than 20 years prior to the IOM report, C. Everett Koop, MD, the U.S. Surgeon General, issued a report noting that government agencies were "very quick to embrace the importance of salt reduction in the 1970s and 1980s, which stood in stark contrast for the snail's pace of recommendations related to reducing blood cholesterol levels."

The authors cited many more studies finding little association between salt and blood pressure that did not eliminate the stigma attached to the mineral.

Advocates for salt reduction questioned the science behind studies that didn't conform to their opinion, and proponents partially blamed the food industry because it was in their best interest to muddy the waters and keep the debate going.

One of the interesting things about this debate, Bayer and colleagues pointed out, was that you could find respected academics on both sides.

"At the most fundamental level, we believe that it is essential to recognize the role that judgment and values must play in evidence-informed policy making," the authors concluded.

"Science must remain open, skeptical, and concerned about unmeasured confounding and selection bias in studies that accompany even the best efforts to articulate the evidence for new interventions," they added.

The investigators said that one of the reviewers of this paper had asked, "In the end, does the harm of exaggerating certainty do more harm than good? After all, it would be very hard to make any policy from a position of informed, complicated, contextualized ambivalence."

They concluded that the "concealment of scientific uncertainty is a mistake that serves neither the ends of science nor good policy. Simplistic pictures of translation from evidence to action distort our ability to understand how policy is, in fact, made and how it should be made."
Read the complete article here.

Another article here.

More data in the Salt Wars - Aug 14, 2014; http://www.medpagetoday.com/Cardiology/Hypertension/47203

An article by Marion Nestle - http://www.foodpolitics.com/2014/08/its-salt-arguments-again-new-research-arguments-over-public-health-recommendations-and-issues-of-conflicts-of-interest/

Thursday, December 6, 2012

The straight dope on cholesterol – Part IX - Attia

 Peter once again provides an excellent summary and then proceeds into Part 9 of his cholesterol tome.

The straight dope on cholesterol – Part IX

The straight dope on cholesterol – Part IX
Previously, across 8 parts of this series we’ve laid the groundwork to ask perhaps the most important question of all:
What should you eat to have the greatest chance of delaying the arrival of cardiovascular disease?
Before we get there, since this series has been longer and more detailed than any of us may have wanted, it is probably worth reviewing the summary points from the previous posts in this series (or you can just skip this and jump to the meat of this post).

What we’ve learned so far

  1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
  2. The pool of cholesterol in our body is essential for life. No cholesterol = no life.
  3. Cholesterol exists in 2 formsunesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
  4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
  5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
  6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control. I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
  7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion. Anyone who tells you different is, at best, ignorant of this topic. At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up. To see an important reference on this topic, please look here.
  8. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
  9. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
  10. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
  11. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells. The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles.
  12. Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the “gut”).
  13. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
  14. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids.
  15. The measurement of cholesterol has undergone a dramatic evolution over the past 70 years with technology at the heart of the advance.
  16. Currently, most people in the United States (and the world for that matter) undergo a “standard” lipid panel, which only directly measures TC, TG, and HDL-C. LDL-C is measured or most often estimated.
  17. More advanced cholesterol measuring tests do exist to directly measure LDL-C (though none are standardized), along with the cholesterol content of other lipoproteins (e.g., VLDL, IDL) or lipoprotein subparticles.
  18. The most frequently used and guideline-recommended test that can count the number of LDL particles is either apolipoprotein B or LDL-P NMR, which is part of the NMR LipoProfile. NMR can also measure the size of LDL and other lipoprotein particles, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels.
  19. The progression from a completely normal artery to a “clogged” or atherosclerotic one follows a very clear path: an apoB containing particle gets past the endothelial layer into the subendothelial space, the particle and its cholesterol content is retained, immune cells arrive, an inflammatory response ensues “fixing” the apoB containing particles in place AND making more space for more of them.
  20. While inflammation plays a key role in this process, it’s the penetration of the endothelium and retention within the endothelium that drive the process.
  21. The most common apoB containing lipoprotein in this process is certainly the LDL particle. However, Lp(a) and apoB containing lipoproteins play a role also, especially in the insulin resistant person.
  22. If you want to stop atherosclerosis, you must lower the LDL particle number. Period.
  23. At first glance it would seem that patients with smaller LDL particles are at greater risk for atherosclerosis than patients with large LDL particles, all things equal.
  24. “A particle is a particle is a particle.” If you don’t know the number, you don’t know the risk.
  25. With respect to laboratory medicine, two markers that have a high correlation with a given outcome are concordant – they equally predict the same outcome. However, when the two tests do not correlate with each other they are said to be discordant.
  26. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study.
  27. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk.
  28. There is no way of determining which individual patient may have discordant LDL-C and LDL-P without measuring both markers.
  29. Discordance between LDL-C and LDL-P is even greater in populations with metabolic syndrome, including patients with diabetes. Given the ubiquity of these conditions in the U.S. population, and the special risk such patients carry for cardiovascular disease, it is difficult to justify use of LDL-C, HDL-C, and TG alone for risk stratification in all but the most select patients.
  30. To address this question, however, one must look at changes in cardiovascular events or direct markers of atherosclerosis (e.g., IMT) while holding LDL-P constant and then again holding LDL size constant. Only when you do this can you see that the relationship between size and event vanishes. The only thing that matters is the number of LDL particles – large, small, or mixed.
  31. HDL-C and HDL-P are not measuring the same thing, just as LDL-C and LDL-P are not.
  32. Secondary to the total HDL-P, all things equal it seems smaller HDL particles are more protective than large ones.
  33. As HDL-C levels rise, most often it is driven by a disproportionate rise in HDL size, not HDL-P.
  34. In the trials which were designed to prove that a drug that raised HDL-C would provide a reduction in cardiovascular events, no benefit occurred: estrogen studies (HERS, WHI), fibrate studies (FIELD, ACCORD), niacin studies, and CETP inhibition studies (dalcetrapib and torcetrapib). But, this says nothing of what happens when you raise HDL-P.
  35. Don’t believe the hype: HDL is important, and more HDL particles are better than few. But, raising HDL-C with a drug isn’t going to fix the problem. Making this even more complex is that HDL functionality is likely as important, or even more important, than HDL-P, but no such tests exist to “measure” this.

Did you say “delay?”

That’s right. The question posed above did not ask how one could “prevent” or eliminate the risk cardiovascular disease, it asked how one could “delay” it. There is a difference. To appreciate this distinction, it’s worth reading this recent publication by Allan Sniderman and colleagues. Allan sent me a copy of this paper ahead of publication a few months ago in response to a question I had posed to him over lunch one day. I asked,
“Allan, who has a greater 5-year risk for cardiovascular disease, a 25 year-old with a LDL-P/apoB in the 99th percentile or a 75-year-old with a LDL-P/apoB in the 5th percentile?”
The paper Allan wrote is noteworthy for at least 2 reasons:
  1. It’s an excellent reminder that age is a paramount risk factor for cardiovascular disease.
  2. It provides a much better (causal) model for atherosclerosis than the typical age-driven models, and explains why age is an important risk factor.
What do I mean by this? Most risk calculators (e.g., Framingham) take their inputs (e.g., age, gender, LDL-C, HDL-C, smoking, diabetes, blood pressure) and calculate a 10-year risk score. If you’ve ever played with these models you’ll quickly see that age drives risk more than any other input. But why? Is there something inherently “risky” about being older?

Sniderman and many others would argue (and I agree) that the reason age is a strong predictor of risk has to do with exposure to apoB particles — LDL, Lp(a), and apoB-carrying remnants. Maybe it’s because I’m a math geek, but such models just seem intuitive to me because I think of most things in life in terms of calculus, especially integrals, the “area under a curve.”

[I once tried to explain to a girlfriend who thought I wasn’t spending enough time with her that my interest in her should be thought of in terms of the area under the curve, rather than any single point in time. That is, think in terms of the integral function, not the point-in-time function. Needless to say, she broke up with me on the spot (in the middle of a parking lot!), despite me drawing a very cool picture illustrating the difference, which I’ve re-created, below.]
The reason age is such a big driver of risk is that the longer your artery walls are exposed to the insult of apoB particles, the more likely they are to be damaged, for all the reasons we covered in Part IV of this series. [This paper also reviews the clinical situation of PCSK9 mutations which builds a very compelling case for the causal model of apoB particles in the development of atherosclerosis].

What does eating have to do with cardiovascular risk?

So now that everyone is on the edge of their seat in anticipation of this punch-line, let me provide two important caveats.
First, there are no long-term studies – either in primary or secondary prevention – examining the exact question we all want to know the answer to with respect to the role of dietary intervention on cardiovascular disease. There are short-term studies, some of which I will highlight, which look at proxies for cardiovascular disease, but all of the long-term studies (looking at secondary prevention), are either drug studies or multiple intervention studies (e.g., cholesterol-lowering drug(s) + blood pressure reducing drug(s) + dietary intervention + exercise + …).
In other words, the “dream” study has not been done and won’t be done for a long time. The “dream” study would follow 2 randomized groups for many years and only make one change between the groups. Group 1 would consume a standard American diet and group 2 would consume a very-low carbohydrate diet. Furthermore, compliance within each group would be excellent (many ways to ensure this, but none of them are inexpensive – part of why this has not been done) and the study would be powered to detect “hard outcomes” (e.g., death), instead of just “soft outcomes” (e.g., changes in apoB, LDL-C, LDL-P, TG).
Second, everything we have learned to date on the risk relationship between cardiovascular disease and risk markers is predicated on the assumption that a risk maker of level X in a person on diet A is the same as it would be for a person on diet B.
Since virtually all of the thousands of subjects who have made up the dozens of studies that form the basis for our understanding on this topic were consuming some variant of the “standard American diet” (i.e., high-carb), it is quite possible that what we know about risk stratification is that this population is not entirely fit for extrapolation to a population on a radically different diet (e.g., a very-low carbohydrate diet or a ketogenic diet). Many of you have asked about this, and my comments have always been the same. It is entirely plausible that an elevated level of LDL-P or apoB in someone consuming a high-carb diet portends a greater risk than someone on a ketogenic or low-carb diet. There are many reasons why this might be the case, and there are many folks who have made compelling arguments for this hypothesis.

But we can’t forget the words of Thomas Henry Huxley, who said, “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.” Science is full of beautiful hypothesis slayed by ugly facts. Only time will tell if this hypothesis ends up in that same graveyard, or changes the way we think about lipoproteins and atherosclerosis.

The role of sugar in cardiovascular disease

Let’s start with what we know, then fill in the connections, with the goal of creating an eating strategy for those most interested in delaying the onset of cardiovascular disease.

There are several short-term studies that have carefully examined the impact of sugar, specifically, on cardiovascular risk markers. Let’s examine one of them closely. In 2011 Peter Havel and colleagues published a study titled Consumption of fructose and HFCS increases postprandial triglycerides, LDL-C, and apoB in young men and women. If you don’t have access to this journal, you can read the study here in pre-publication form. This was a randomized trial with 3 parallel arms (no cross-over). The 3 groups consumed an isocaloric diet (to individual baseline characteristics) consisting of 55% carbohydrate, 15% protein, and 30% fat. The difference between the 3 groups was in the form of their carbohydrates.

Group 1: received 25% of their total energy in the form of glucose
Group 2: received 25% of their total energy in the form of fructose
Group 3: received 25% of their total energy in the form of high fructose corn syrup (55% fructose, 45% glucose)

The intervention was relatively short, consisting of both an inpatient and outpatient period, and is described in the methodology section.

Keep in mind, 25% of total energy in the form of sugar is not as extreme as you might think. For a person consuming 2,400 kcal/day this amounts to about 120 pounds/year of sugar, which is slightly below the average consumption of annual sugar in the United States. In that sense, the subjects in Group 3 can be viewed as the “control” for the U.S. population, and Group 1 can be viewed as an intervention group for what happens when you do nothing more in your diet than remove sugar, which was the first dietary intervention I made in 2009.

Despite the short duration of this study and the relatively small number of subjects (16 per group), the differences brought on by the interventions were significant. The figure below shows the changes in serum triglycerides via 3 different ways of measuring them. Figure A shows the difference in 24-hour total levels (i.e., the area under the curve for serial measurements – hey, there’s our integral function again!). Figure B shows late evening (post-prandial) differences. Figure C shows the overall change in fasting triglyceride level from baseline (where sugar intake was limited for 2 weeks and carbohydrate consumption consisted only of complex carbohydrates).
impact on TG
The differences were striking. The group that had all fructose and HFCS removed from their diet, despite still ingesting 55% of their total intake in the form of non-sugar carbohydrates, experienced a decline in total TG (Figure A, which represents the daily integral of plasma TG levels, or AUC). However, that same group experienced the greatest increase in fasting TG levels (Figure C). Post-prandial TG levels were elevated in all groups, but significantly higher in the fructose and HFCS groups (Figure B). The question this begs, of course, is which of these measurements is most predictive of risk?

Historically, fasting levels of TG are used as the basis of risk profiling (Figure C), and according to this metric glucose consumption appears even worse than fructose or HFCS. However, recent evidence suggests that post-prandial levels of TG (Figure B) are a more accurate way to assess atherosclerotic risk, as seen here, here, and here. One question I have is why did the AUC calculations in Figure A show a reduction in plasma TG level for the glucose group?

The figure below summarizes the differences in LDL-C, non-HDL-C, apoB, and apoB/apoA-I.
impact on lipoproteins
Again, the results were unmistakable with respect to the impact of fructose and HFCS on lipoproteins, and by extension, the relative lack of harm brought on by glucose in isolation. [Of course, removal of glucose and fructose/HFCS would have been a very interesting control group.]
One of the simultaneous strengths and weaknesses of this study was the heterogeneity of its subjects, who ranged in BMI from 18 to 35, in age from18 to 40, and in gender. While this provided at least one interesting example of age-related differences in carbohydrate metabolism (older subjects had a greater increase in triglycerides in response to glucose than younger subjects), it may have actually diluted the results. There were also significant differences between genders in the glucose group.
What was most interesting about this study was the clear difference between the 3 groups that was not solely a function of fructose load. In other words, the best outcome from a disease risk standpoint was in the glucose group, while the worst outcome was not in the all-fructose group, but in the 50/50 (technically 55/45) mixed group. This is a very powerful indication that while glucose and fructose alone can be deleterious in excess, their combination seems synergistically bad.

The role of saturated fat in cardiovascular disease

In the next week or two I’ll be posting an hour-long comprehensive lecture I gave at UCSD a few weeks ago on this exact topic. Rather than repeat any of it here, I’ll highlight one study that I did not include in that lecture. The study, Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease, published in 2003, treated 23 obese patients (average BMI 39) with known cardiovascular disease (status post coronary artery bypass surgery and/or stent placement) with a high-fat ketogenic diet. Because the study was free-living and relied on self-reporting, not all subjects had documented levels of elevated serum B-OHB. However, the subjects were instructed to avoid starch and consume 50% of their caloric intake via saturated fat, primarily in the form of red meat and cheese. There were no restrictions on fruits and vegetables, which may have accounted for the observation that not all subjects were ketotic during the 6-week intervention. In total, only 5 of the 23 patients achieved documented ketosis.
All of the subjects were on statins and entered the study at a goal LDL-C level target of 100 mg/dL, which may have been the only way the authors could get the IRB to approve such a study.
The table below shows the changes in lipoprotein fractions following the intervention (there was no control group):
Table 2
This study was conducted during the height of the “outcry” over the Atkins diet. While most doctors reluctantly agreed that Dr. Atkins’ diet could reduce body fat, most believed it was still very dangerous. In the words of Dean Ornish, “Sure you can lose weight on a low-carb diet, but you can also lose weight on heroin and no one would recommend that!”

Fair point. In fact, the authors of this study acknowledged that they “strongly expected” this dietary intervention to increase risk for cardiovascular disease, which is why they only included subjects on statins with low LDL-C. However, as you can see from the table above, the authors were startled by the results. The subjects experienced a significant reduction in plasma triglycerides and VLDL triglycerides, without an increase in LDL-C or LDL-P. In fact, LDL size and HDL size increased and VLDL size decreased – all signs of improved insulin resistance. Furthermore, fasting glucose and insulin levels also decreased significantly. The mean HOMA-IR was reduced from 5.6 to 3.6 (normal is 1.0) and TG/HDL-C from 3.3 to 2.0 (normal is considered below 3, but “ideal” is probably below 1.0) in just 6 weeks. Taken together, these changes, combined with the dramatic change in VLDL size, suggest insulin resistance was dramatically improved while consuming a diet of 50% saturated fat!

As all of these patients were taking statins, we’re really robbed of seeing the impact of this diet on LDL-P, which did not change. Also, CRP levels rose (though not clinically or statistically significantly).

Putting it all together

It is very difficult to make the case that when carbohydrates in general, and sugars in particular, are removed or greatly reduced in the diet, insulin resistance is not improved, even in the presence of high amounts of saturated fats. When insulin resistance improves (i.e., as we become more insulin sensitive), we are less likely to have the signs and symptoms of metabolic syndrome. As we meet fewer criteria of metabolic syndrome, our risk of not only heart disease, but also stroke, cancer, diabetes, and Alzheimer’s disease goes down.

Furthermore, as this study on the Framingham cohort showed us, the more criteria you have along the spectrum of metabolic syndrome, the more difficult it becomes to predict your risk, due to a widening gap in discordant risk markers, as shown in this figure.
LDL-C vs. LDL-P in MS
As I noted at the outset, the “dream” trial has not yet been done, though we (NuSI) plan to change that. Until then each of us has to make a decision several times every day about what we will and won’t put in our mouths. Much of this blog is dedicated to underscoring the impact of carbohydrate reduction on insulin resistance and metabolic syndrome.

The results of the trials to date, combined with a nuanced understanding of the lipoprotein physiology and their role on the atherosclerotic disease process, bring us to the following conclusions:
  1. The consumption of sugar (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I.
  2. The removal of sugar reverses each of these.
  3. The consumption of fructose alone, though likely in dose-dependent fashion, has a similar, though perhaps less harmful, impact as that of fructose and glucose combined (i.e., sugar).
  4. The addition of fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease.
  5. The higher the level of serum triglycerides, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).
  6. The greater the number (from 0 to 5) of inclusion criteria for metabolic syndrome, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).
I would like to address one additional topic in this series before wrapping it up – the role of pharmacologic intervention in the treatment and prevention of atherosclerotic disease, so please hold off on questions pertaining to this topic for now.

Read the complete article here.